..We now review recent developments in understanding of genetic forms of severe insulin resistance and/or lipodystrophy and suggest a revised classification based on growing knowledge of the underlying pathophysiology...

..These hormones come from three major sites-fat cells, the gastrointestinal tract, and the pancreas. In this Review we provide a synthesis of recent evidence concerning the actions of these hormones on food intake...

Human obesity as a heritable disorder of the central control of energy balance

..Indeed, we hope that they may eventually lead to improved treatment for patients and, in addition, help to inculcate a more enlightened attitude to the obese with a reduction in their experience of social and economic discrimination...

..Ultimately, this is a potential route to treatment of both disease types. This approach is discussed in relation to Type 2 diabetes, arising from both insufficient insulin production and insulin resistance...

..Moreover, the findings of the present study identify an important additional mechanism via which the C/EBP transcription factors may control a network of gene expression regulating adipogenesis, lipogenesis and insulin sensitivity...

..The specific reduction in the SREBP1c isoform seen in the adipose tissue of obese and type 2 diabetic subjects can be recapitulated ex vivo by TNF-alpha, suggesting a possible mechanism for this association...

ETO/MTG8 is an inhibitor of C/EBPbeta activity and a regulator of early adipogenesis

..A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined...

..The phenotypic similarities between patients with SIM1 deficiency and melanocortin 4 receptor (MC4R) deficiency suggest that some of the effects of SIM1 deficiency on energy homeostasis are mediated by altered melanocortin signaling. ..

Energy expenditure and adaptive responses to an acute hypercaloric fat load in humans with lipodystrophy

..Deletion carriers exhibited hyperphagia and severe insulin resistance disproportionate for the degree of obesity. We show that copy number variation contributes significantly to the genetic architecture of human obesity...

A comparative study of the central effects of specific proopiomelancortin (POMC)-derived melanocortin peptides on food intake and body weight in pomc null mice

..Although other melanocortins can reduce food intake in the short-term, only alpha-MSH can reduce the excess fat and lean mass found in Pomc-/- mice, mediated largely through an effect on food intake...

Studies of the peptide YY and neuropeptide Y2 receptor genes in relation to human obesity and obesity-related traits

..01). In conclusion, mutations in PYY and Y2R are not commonly found in humans with severe early-onset obesity. The relationship between common variants in Y2R and obesity-related traits deserves further exploration in other populations...

..We describe a role for FTO in the coupling of amino acid levels to mammalian target of rapamycin complex 1 signaling. These findings suggest that FTO may influence body composition through playing a role in cellular nutrient sensing...

..However, the clinical spectrum and mode of inheritance have not been defined, pathophysiological mechanisms leading to obesity are poorly understood, and there is little information regarding genotype-phenotype correlations...

..39 mM) than wild-type subjects (1.47 mM) (P < 0.01). These findings suggest a previously unexpected role for this orphan receptor in the regulation of lipid metabolism that warrants further investigation...

The Wnt antagonist Dickkopf-1 and its receptors are coordinately regulated during early human adipogenesis

..Given the public health importance of disorders of adipose mass, further knowledge of the pathways involved specifically in human adipocyte differentiation might ultimately be of clinical relevance...

A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance

..Obese children carrying the Tyr221Cys variant were hyperphagic and showed increased linear growth, both of which are features of MC4R deficiency. These studies support a role for beta-MSH in the control of human energy homeostasis...

..In a mouse model which lacks all endogenous POMC peptides, s.c. treatment with synthetic 1-28 POMC alone can reduce food intake and body weight, but has no impact upon adrenal growth or steroidogenesis...

..191. We conclude that loss of one copy of the POMC gene predisposes to obesity in humans. Thus, genetic variants having relatively subtle effects on POMC expression and function could influence susceptibility to obesity...

Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile

..Importantly, this provide the first indication that selective alteration of FTO levels in the hypothalamus can influence food intake, a finding consistent with the reported effects of FTO alleles on appetite and food intake in man...

..9%, respectively. In conclusion, mutations in 5HT2c are unlikely to be a common cause of severe early-onset human obesity. The identification of several novel polymorphisms at this locus may aid future genetic epidemiological studies...

Mitochondrial oxidative phosphorylation is impaired in patients with congenital lipodystrophy

..The genes affected in these monogenic disorders all encode ligands and receptors of the highly conserved leptin-melanocortin pathway, which is critical for the regulation of food intake and body weight...

..We thus set out to determine the prevalence of diabetes and insulin resistance among patients with PCNT defects and examined the effects of pericentrin depletion on insulin action using 3T3-L1 adipocytes as a model system...

Role of the POZ zinc finger transcription factor FBI-1 in human and murine adipogenesis